Topical or other local application of potent glucocorticoids can produce severe toxic effects such as Cushingoid features, pituitary-adrenal suppression, skin atrophy, immunosuppression and inhibition of wound healing. Other kinds of toxic responses, including allergies and cataracts, have resulted from long term use of drugs of this type.
Ophthalmic application of glucocorticosteroids presents additional problems. The protective mechanisms built into the eye allow only small amounts of doses applied to the eye to reach the target sites within the eye; generally, over 90 per cent of the total dose will find its way into the general circulation. This in turn leads to serious systemic side effects of the type described above. Moreover, there is a more serious and specific side effect when these drugs are used in the eye, which is an increase in intraocular pressure (IOP). Corticosteroid-induced chronic or acute glaucoma has in fact been reported since the early 1960's. Generally, the corticosteroid is needed only topically to control the inflammation. However, the absorbed steroid is responsible for the serious side effects noted above. It is believed that the effect of the corticosteroid on the aqueous outflow pathway and adjacent tissue glycosaminoglycans (GAG's) is important in the development of glucocorticoid-induced ocular hypertension.
There is therefore a serious need for potent local anti-inflammatory steroids which lack systemic activity and consequently do not produce the serious systemic side effects associated with drugs of this class.
The natural glucocorticosteroids and many of their marketed derivatives are .DELTA..sup.4 and .DELTA..sup.1,4 pregnenes having 21-hydroxy substituents. There are, however, a number of anti-inflammatory .DELTA..sup.4 and .DELTA..sup.1,4 androstenes described in the literature. Thus, Anner et al, U.S. Pat. No. 3,636,010, patented Jan. 18, 1972, describes esters of .DELTA..sup.4 and .DELTA..sup.1,4 -16.alpha.-methyl-6.alpha.,9.alpha.-difluoro-11.beta.,17.alpha.-dihydroxy- 3-oxo-androstadiene-17-carboxylic acid having "good anti-inflammatory and thymolytic activity." Thymolytic activity is, however, an indication of systemic activity.
In the 1970's and early 1980's several patents have issued describing androstene derivatives which have been purported to have more desirable ratios of anti-inflammatory activity to undesirable side effects. These include British Patent Specification No. 1,384,372; Phillipps et al U.S. Pat. No. 3,828,080; Phillipps et al U.S. Pat. No. 3,856,828; Phillipps et al U.S. Pat. No. 4,093,721; UK Patent Application GB 2,014,579; Edwards U.S. Pat. No. 4,188,385; Alvarez U.S. Pat. No. 4,198,403; and Edwards U.S. Pat. No. 4,263,289. The .DELTA..sup.4 and .DELTA..sup.1,4 3-oxoandrostene derivatives of these patents may bear various substituents at the 6, 9, 11 and 16 positions and typically possess a 17.alpha.-hydroxy or 17.alpha.-alkanoyloxy substituent. The 17.beta.-grouping is variously a carboxylic acid alkyl ester, a carboxylic acid haloalkyl ester or a thiocarboxylic acid alkyl ester. In British Patent Specification No. 1,578,243 and its U.S. counterpart, Kalvoda et al U.S. Pat. No. 4,285,937, there are also described androstadiene-17-carboxylic acids and their esters. The Kalvoda et al compounds are represented in the '937 patent as novel esters of androstadiene 17-carboxylic acids of the formula ##STR1## wherein R' represents a free hydroxyl group or a hydroxyl group which is esterified with a carboxylic acid having not more than 7 carbon atoms, R" represents a methyl group in the .alpha.- or .beta.- position or the methylene group, R is H or Cl, each of X and Y represents a hydrogen, chlorine or fluorine atom, with the proviso that at least one of these substituents is one of these halogens, when R is Cl, and that Y is only Cl or F and X only Cl, when R is H and that the androstadiene-17-carboxylic acid ester group does not contain more than 11 carbon atoms. These compounds are said to have pronounced anti-inflammatory action coupled with remarkedly low systemic side effects and to be especially suitable for dermatological use. The esters of the steroid 17-carboxylic acids are derived from alcohols containing 1 to 10 carbon atoms of the aliphatic, araliphatic and heterocyclic type which are unsubstituted or substituted by chlorine, fluorine, bromine, hydroxyl, lower alkoxy or lower alkanoyloxy; these alcohols are said to include the lower alkanols (methanol, ethanol, isopropanol etc.). The 17-ester group can also be chloromethoxycarbonyl, fluoromethoxycarbonyl or 2-chloro or 2-fluoroethoxycarbonyl. The esterified hydroxy group R' is said to be derived from a saturated or unsaturated C.sub.1 -C.sub.7 carboxylic acid which is unsubstituted or substituted by halogen atoms, hydroxyl or lower alkoxy groups; named as examples of R' are formyloxy, acetoxy, propionyloxy, butyryloxy, valeryloxy, diethylacetoxy, caproyloxy, chloroacetoxy, chloropropionyloxy, oxypropionyloxy or acetoxypropionyloxy. However, the only specific compound in which the 2-position is unsubstituted which is disclosed by Kalvoda et al is methyl 9.alpha.-chloro-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17 .alpha.-propionyloxyandrosta-1,4-diene-17-carboxylate. Indeed, all of Kalvoda et al's specific compounds are 17.alpha.-propionyloxy compounds. In view of the fact that Kalvoda et al's compounds are expected to hydrolyze in vivo to release the acid from which the 17.alpha.-ester is derived, it is not surprising that the acid preferred by Kalvoda et al for derivatizing the 17.alpha.-hydroxyl is propionic acid, which is known to have an LD.sub.50 in rats of only 4.29 g/kg orally. Acetic acid, which is also basically non-toxic, has an LD.sub.50 in rats of 3.53 g/kg orally. In contrast, the oral LD.sub.50 in rats of chloroacetic acid is 76 mg/kg, which is relatively quite toxic.
More recently, soft steroids have been developed in an effort to provide compounds having potent anti-inflammatory activity with minimal systemic activity. These compounds include .DELTA..sup.4 and .DELTA..sup.14 17.alpha.-alkoxy-11.beta.-hydroxy-3-oxoandrostenes optionally bearing various substituents at the 6,9 and 16-positions and related 11-substituted compounds which are esters or thioesters of 17.beta.-carboxylic acids. These 17.alpha.-ethers are described in Bodor U.S. Pat. No. 4,710,495. Preferred compounds are taught to be the haloalkyl esters of 17.alpha.-alkoxy-11.beta.-hydroxyandrost-4-en-3-one-17.beta.-carboxylic acids.
Another series of soft steroids which are described as having potent anti-inflammatory activity with minimal systemic activity are the 17.alpha.-carbonates of Bodor U.S. Pat. No. 4,996,335. These compounds include as preferred embodiments haloalkyl 17.alpha.-alkoxycarbonyloxy-11.beta.-hydroxyandrost-4-en-3-one-17.beta.-ca rboxylates and the corresponding .DELTA..sup.14 compounds, optionally bearing 6.alpha.- and/or 9.alpha.-fluorine and 16.alpha.- or 16.beta.-methyl substituents. One of these compounds is chloromethyl 17.alpha.-ethoxycarbonyloxy-11.beta.-hydroxyandrosta-1,4-dien-3-one-17.bet a.-carboxylate, also known as loteprednol etabonate, for which clinical development has been completed and which is awaiting final FDA approval.
Nevertheless, there remains a serious need in this art for new anti-inflammatory steroids which have potent local anti-inflammatory activity while having minimal or non-existent systemic activity.